Abstract：
Multiple primary tumors (MPTs) are a harbinger of hereditary cancer syndromes. Affected individuals often fit genetic testing criteria for a number of hereditary cancer genes and undergo multigene panel testing. Other genomic testing options, such as whole exome (WES) and whole genome sequencing (WGS) are available, but the utility of these genomic approaches as a second-tier test for those with uninformative multigene panel testing has not been explored. Here, we report our germline sequencing results from WGS in 9 patients with MPTs who had non-informative multigene panel testing. Following germline WGS, sequence (agnostic or 735 selected genes) and copy number variant (CNV) analysis was performed according to the American College of Medical Genetics (ACMG) standards and guidelines for interpreting sequence variants and reporting CNVs. In this cohort, WGS, as a second-tier test, did not identify additional pathogenic or likely pathogenic variants in cancer predisposition genes. Although we identified a CHEK2 likely pathogenic variant and a MUTYH pathogenic variant, both were previously identified in the multigene panels and were not explanatory for the presented type of tumors. CNV analysis also failed to identify any pathogenic or likely pathogenic variants in cancer predisposition genes. In summary, after multigene panel testing, WGS did not reveal any additional pathogenic variants in patients with MPTs. Our study, based on a small cohort of patients with MPT, suggests that germline gene panel testing may be sufficient to investigate these cases. Future studies with larger sample sizes may further elucidate the additional utility of WGS in MPTs.
摘要：
多原发肿瘤（MPT）是遗传性癌症综合征的先兆。受影响的个体通常符合许多遗传性癌症基因的遗传测试标准，并接受多基因小组测试。其他基因组测试选项，如全外显子组(WES)和全基因组测序(WGS)可用，但是，这些基因组方法作为对那些没有信息的多基因小组测试的第二层测试的实用性尚未被探索。这里,我们报告了9例接受非信息性多基因组检测的MPT患者的WGS种系测序结果.在种系WGS之后，根据美国医学遗传学学会(ACMG)解释序列变异和报告CNV的标准和指南,进行序列(不可知或735个选定基因)和拷贝数变异(CNV)分析.在这个队列中，WGS,作为第二层测试，未在癌症易感性基因中鉴定出其他致病性或可能的致病性变异。虽然我们确定了CHEK2可能的致病变异体和MUTYH致病变异体，两者先前在多基因小组中被鉴定,并且不能解释所呈现的肿瘤类型.CNV分析也未能鉴定癌症易感性基因中的任何致病性或可能的致病性变体。总之,在多基因小组测试之后，WGS在MPT患者中没有发现任何其他致病变异。我们的研究,基于一小群MPT患者，表明种系基因组测试可能足以调查这些病例。未来更大样本量的研究可能会进一步阐明WGS在MPT中的额外效用。
